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WO2008040361A2 - Utilisation d'une combinaison de médicaments induisant une hypothermie - Google Patents

Utilisation d'une combinaison de médicaments induisant une hypothermie Download PDF

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Publication number
WO2008040361A2
WO2008040361A2 PCT/DK2007/050138 DK2007050138W WO2008040361A2 WO 2008040361 A2 WO2008040361 A2 WO 2008040361A2 DK 2007050138 W DK2007050138 W DK 2007050138W WO 2008040361 A2 WO2008040361 A2 WO 2008040361A2
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alkyl
substituted
phosphate
alkenyl
methyl
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PCT/DK2007/050138
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WO2008040361A3 (fr
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Uno Jakob Weber
Jacob Gotfredsen
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Neurokey A/S
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Priority to US12/311,578 priority Critical patent/US20100029739A1/en
Priority to EP07817937A priority patent/EP2083807A2/fr
Publication of WO2008040361A2 publication Critical patent/WO2008040361A2/fr
Publication of WO2008040361A3 publication Critical patent/WO2008040361A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of a combination of compounds for the induction of hypothermia for the prophylaxis and treatment of ischemia.
  • Ischemia is the lack of oxygenated blood flow to various body parts and may result from apoplexia, cardiac arrest and asphyxia.
  • Cerebral ischemia is an ischemic condition where the brain or parts of the brain do not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various serious diseases such as stroke and cardiac arrest, or the result of arterial obstruction such as strangulation. Severe or prolonged cerebral ischemia will result in unconsciousness, brain damage or death.
  • hypothermia counteracts ischemic brain damage by several mechanisms:
  • Ischemia induces opening of the blood-brain barrier, a process that seems to be very sensitive to brain temperature [15]. This is evident from studies of tracers and their migration across the blood-brain barrier, in which hypothermia attenuates extravasation several hours after ischemia [16] and prevents vasogenic oedema [17]. 2. Reperfusion after brain ischemia results in the production of free radicals, which causes peroxidation and destruction of membrane lipids [18]. Hypothermia prevents the production of free radicals such as hydroxyl and nitric oxide during reperfusion after brain ischemia [19;20;24].
  • Amino acids such as glutamate, aspartate, and glycine, act as excitotoxic neurotransmitters by over stimulation of neurons in the vicinity of ischemic damage, which causes further injury. Hypothermia lowers the release and may even cause a more rapid reuptake of these transmitters [21 -23].
  • hypothermia By lowering of neutrophil and microglial activation after ischemia, hypothermia also has an anti-inflammatory effect [30;31].
  • Apoptosis and DNA changes are crucial stages in delayed neuronal death after transient cerebral ischemia [32].
  • Hypothermia directly inhibits apoptosis [33] and may also increase endogenous production of the anti-apoptotic protein Bcl-2 [34].
  • Hypothermia may even have effects at the DNA level: A slight lowering of brain temperature results in less DNA fragmentation [35] and less apoptosis [36].
  • hypothermia Induction of hypothermia by lowering of the core temperature of the body has been attempted by mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel.
  • mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel.
  • these mechanical inducers of hypothermia have been shown to have considerable unwanted side effects. These side effects include shivering, serious infections and lung puncture. Shivering causes an increased exertion of the heart of the patient, and this will in some cases result in ischemia of the heart and thereby increased morbidity and mortality.
  • a pharmaceutical composition comprising a combination of compounds capable of inducing hypothermia would not only solve the problem of reducing or preventing the effects of ischemia, such as tissue damaging effects, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
  • the present invention relates to the induction of hypothermia in humans in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising a combination of compounds capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue anoxia.
  • a pharmaceutical composition comprising a combination of compounds capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue anoxia.
  • the inventors have found that such hypothermic effects can be obtained in humans as a result of two classes of compounds:
  • Vanilloid receptor agonists capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors
  • the present invention discloses the use of a combination of compounds, wherein at least one compound is a vanilloid receptor agonist and at least one other compound is a cannabinoid and/or cannabimimetic compound, for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual.
  • a kit of parts comprising the medicament as herein disclosed is yet an aspect of the present invention.
  • a vanilloid receptor agonist is a vanilloid compound.
  • a cannabinoid receptor agonist is a cannabinoid or a cannabimimetic compound.
  • a vanilloid receptor antagonist is a substance capable of inhibiting the effect of a vanilloid receptor agonist.
  • a cannabinoid receptor antagonist is a substance capable of inhibiting the effect of a cannabinoid receptor agonist.
  • Alcohol A class of organic compounds containing one or more hydroxyl groups (OH).
  • OH hydroxyl groups
  • Alicvclic group means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
  • Aliphatic group in the context of the present invention, the term "aliphatic group” means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
  • Alkoxyl group the term alkoxyl group or alkoxy covers an alkyl linked to a larger moiety by oxygen.
  • Alkyl group means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like.
  • Alkenyl group means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group.
  • Alkvnyl group means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.
  • Amphiphil substance containing both polar, water-soluble and nonpolar, water- insoluble groups.
  • Aromatic group the term "aromatic group” or "aryl group” means a mono- or polycyclic aromatic hydrocarbon group.
  • Cannabinoid Compound capable of binding to a cannabinoid receptor and isolated from or identical to a compound isolated from an organism such a plant or animal. In the present context any compound capable of binding a cannabinoid receptor. Also, the term cannabinoid is used as a general term covering both cannabinoid and cannabimimetic compounds.
  • Cannabimimetic Compound capable of binding to a cannabinoid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a cannabinoid receptor.
  • Capsaicinoid Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and isolated from or identical to a compound isolated from an organism such as a plant or animal. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor.
  • a capsaicinoid may also be referred to as a vanilloid receptor agonist.
  • Capsaicinoid-like Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor. A capsaicinoid-like compound may also be referred to as a vanilloid receptor agonist.
  • Combination of compounds Herein the term generally covers a combination of at least one vanilloid receptor agonist and at least one cannabinoid and/or cannabimimetic compound. The term may also include combinations of other compounds or drugs or the like.
  • Compound A chemical substance formed from two or more elements, held together by chemical bonds, with a fixed ratio determining the composition. The elements lose their individual chemical properties and the compound has new properties.
  • vanilloid receptor agonist a term covering all of the following: vanilloid receptor agonist, capsaicinoid, capsaicinoid-like, cannabinoid and cannabimimetic compound.
  • Cyclic group means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
  • Cvcloalkenyl means a monovalent unsaturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkenyl, lower alkoxy, lower haloalkoxy, alkenylthio, halo, haloalkenyl, hydroxyalkenyl, nitro, alkoxycarbonenyl, amino, alkenylamino, alkenylsulfonyl, arylsulfonyl, alkenylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkenylaminocarbonyl, arylaminocarbonyl, alkenylcarbonylamino and arylcarbonylamino.
  • Cvcloalkyl means a monovalent saturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino- sulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino.
  • Cationic group A chemical group capable of functioning as a proton donor when a compound comprising the chemical group is dissolved in a solvent, preferably when dissolved in water.
  • Form a ring means that the atoms mentioned are connected through a bond when the ring structure is formed.
  • Group (Moiety / substitution) as is well understood in this technical area, a large degree of substitution is not only tolerated, but is often advisable. Substitution is anticipated on the materials of the present invention.
  • group and “moiety” are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not allow or may not be so substituted.
  • group when the term "group” is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with O, N, or S atoms, for example, in the chain as well as carbonyl groups or other conventional substitution.
  • alkyl group is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc.
  • alkyl group includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc.
  • alkyl moiety is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like.
  • alkenyl group and “alkenyl moiety”; to "alkynyl group” and “alkynyl moiety”; to "cyclic group” and “cyclic moiety; to "alicyclic group” and “alicyclic moiety”; to "aromatic group” or “aryl group” and to “aromatic moiety” or “aryl moiety”; as well as to "heterocyclic group” and “heterocyclic moiety”.
  • Heterocyclic group means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulphur, etc.).
  • Heterocyclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N, O or S(O) 0 . 2 , and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino,
  • Heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulphur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, aryl- aminocarbonyl, alkylcarbonlamino and arylcarbonylamino.
  • Ischemia Restriction in blood supply with resultant dysfunction or damage of tissue.
  • Moieties of a particular compound cover group(s) or part(s) of said particular compound.
  • composition refers to any chemical or biological material, compound, composition or combinations of any of these especially combinations of compounds, capable of inducing a desired therapeutic effect when properly administered to a patient.
  • Some drugs are sold in an inactive form that is converted in vivo into a metabolite with pharmaceutical activity.
  • pharmaceutical composition and “medicament” encompass both the inactive drug and the active metabolite.
  • Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
  • Vanilloid receptor agonist A capsaicinoid or capsaicinoid-like compound capable of binding a vanilloid receptor / capsaicinoid receptor.
  • the principle of the present invention is the use of a combination of vanilloid receptor agonists and cannabinoids and/or cannabimimetic compounds for induction of hypothermia for alleviating the effects of ischemia, such as but not limited to tissue damaging effects of ischemia.
  • Ischemia is the reduction or abolition of blood supply to a tissue.
  • the associated deficiency of oxygen and nutrients may lead to cell death (necrosis) in areas of the affected tissue.
  • the damage induced by the lack of oxygenated blood in the brain occurs in two stages. First cellular metabolism is arrested due to lack of oxygen and some cells and tissue will die within minutes as a consequence hereof. Secondly a cascade of processes such as apoptosis are initiated and continue up to 12 hours after the event that initially induced the ischemic state has been abolished.
  • the tissue damaged by the second cascade can be crucial and cause greater harm to the individual than the primary damage happening within the first minutes of ischemia.
  • the current invention is aimed at correcting ischemia of the brain thereby minimizing the damage to the central nervous system.
  • the invention does so by administering a drug to induce hypothermia in patients.
  • the hypothermic effect is presumed to counteract ischemic damage by several mechanisms in the brain: Prevention of the blood-brain-barrier disruption that happens soon after ischemic onset that allows oedema formation from extravasation; Diminishing of the oxygen-based free-radical production; Reduction of the excitotoxic-neurotransmitter release that overstimulates neighboring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action. Induction of hypothermia has a neuroprotective effect.
  • Ischemia may occur under various circumstances; of special relevance to the present invention are the circumstances relating to cardiovascular diseases, asphyxia and traumatic brain injuries.
  • compounds of the present invention is administered to prevent or treat or treat and prevent tissue damaging effects subsequent or in conjunction with ischemia.
  • Cardiovascular disease is the most common cause of death and of physical as well as mental impairment in the developed world. A similar development is seen in the rest of the world as it emulates the lifestyle of the Western hemisphere with its fatty diets, lack of exercise and increasing average lifespan.
  • cardiovascular diseases myocardial infarction, acute coronary syndrome, cardiac arrest and stroke, but many less common cardiovascular diseases may be equally detrimental to the individual affected. These less common diseases include among others arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • Myocardial infarction (heart attack) is a result of an atherosclerotic plaque slowly building up in the inner lining of a coronary artery which then suddenly ruptures, partially or totally occluding the artery and preventing blood flow.
  • Cardiac arrest is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively. Brain damage is likely to occur after 3-4 minutes without medical intervention, except in cases of hypothermia.
  • Stroke is an acute neurological injury, lasting more than 24 hours, in which the blood supply to a part of the brain is interrupted, either by a clot in the artery or if the artery bursts.
  • Arterial aneurism is a localized ballooning of an artery by more than 50% of the diameter of the vessel. Aneurysms most commonly occur in the arteries at the base of the brain and in the aorta. This bulge in an artery carries the risk of bursting and leading to internal hemorrhage. The larger an aneurysm becomes, the more likely it is to burst.
  • Subarachnoid haemorrhage is bleeding into the subarachnoid space surrounding the brain, i.e., the area between the arachnoid and the pia mater. It may arise due to trauma or spontaneously, and is a medical emergency, which can lead to death or severe disability even if recognized and treated in an early stage.
  • Arteriosclerosis is a disease in which arterial walls harden over years or decades as a result of the formation of collagen and calcium deposits.
  • Hypertension or high blood pressure is a medical condition wherein the blood pressure is chronically elevated.
  • Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is a derangement that can contribute to many forms of disease, most notably cardiovascular disease.
  • Arrhythmia is a group of conditions in which the muscle contraction of the heart is irregular or is faster or slower than normal. Some arrhythmias are life threatening medical emergencies that can cause cardiac arrest and sudden death. Cardiomegaly is a medical condition wherein the heart is enlarged. It can often be associated with other serious medical conditions. Cardiomyopathy is the deterioration of the function of the myocardium (i.e., the actual heart muscle). People with cardiomyopathy are at risk of arrhythmia and/or sudden cardiac death.
  • Heart valve regurgitation also known as heart valve insufficiency, is the abnormal leaking of blood through heart valves.
  • Heart valve stenosis is a heart condition caused by the incomplete opening of a heart valve, typically the aortic valve or the mitral valve, impairing blood flow through the heart.
  • Each of the cardiovascular diseases mentioned, as well as others not mentioned, may cause ischemia of organs. This ischemia, whether of the brain, heart or other organs, may lead to death or impairment if not treated rapidly.
  • cardiovascular diseases such as, but not limited to: myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • the medicament is for the treatment or prophylaxis of ischemia due to cardiac arrest, myocardial infarction, stroke, arterial aneurisms, sub-arachnoid haemorrhage or angina pectoris.
  • Sudden cardiac arrest victims may be subjected to early CPR, early defibrillation and early advanced care. Further tests and treatments may include cardiac catheterization, electrophysiologic tests, coronary artery bypass surgery, balloon angioplasty or PTCA, antiarrhythmic medicine, implantable cardioverter / defibrillator, implantable pacemaker and heart transplant.
  • acute treatment may include clot-busters (e.g. tPA) or surgical intervention (e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils”).
  • clot-busters e.g. tPA
  • surgical intervention e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils”
  • Preventive treatment includes the administration of anticoagulants/anti-platelet. It may furthermore include carotid endarterectomy and angioplasty and/or stents.
  • Patients suffering a heart attack may have one or several treatments and procedures done to survive and diagnose the condition: These include resuscitation (early CPR, early defibrillation, early advanced care), thrombolysis, coronary angioplasty (also known as Percutaneous Transluminal Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation), and coronary artery bypass graft surgery (CABG).
  • resuscitation early CPR, early defibrillation, early advanced care
  • thrombolysis also known as Percutaneous Transluminal Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation
  • PTCA Percutaneous Transluminal Coronary Angioplasty
  • PCI Percutaneous Coronary Interventions
  • Balloon Angioplasty and Coronary Artery Balloon Dilation Balloon Angioplasty and Coronary Artery Balloon Dilation
  • Asphyxia is a common cause of death and of physical as well as mental impairment in newborns, children and adults of all ages.
  • Asphyxia can be divided into perinatal asphyxia and non-perinatal asphyxia:
  • Perinatal asphyxia is the medical condition resulting from deprivation of oxygen to a newborn infant long enough to cause apparent harm. It results most commonly from a drop in maternal blood pressure or interference during delivery with blood flow to the infant's brain. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Extreme degrees of asphyxia can cause cardiac arrest and death. Hypoxic damage can occur to most of the infant's organs, but brain damage is of most concern and perhaps the least likely to quickly and completely heal.
  • Non- perinatal asphyxia is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Common causes hereof include drowning, strangulation and exposure to toxic gasses. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. The absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death.
  • Treatment by administration of the medicament defined in this patent may be carried out in conjunction with test and treatments of diseases and accidents including asphyxia (perinatal asphyxia, and non-perinatal asphyxia including, but not limited to, drowning, strangulation and exposure to toxic gasses).
  • diseases and injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
  • Traumatic brain injury also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage.
  • TBI can result from a closed head injury or a penetrating head injury.
  • Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem.
  • Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain.
  • Outcome can be anything from complete recovery to permanent disability or death. Ischemia is a significant factor contributing to the neurological damage frequently seen in patients suffering from TBI.
  • Treatment by administration of the medicament defined in this patent may also be carried out in conjunction with test and treatments in relation to traumatic head injury (closed head injury or penetrating head injury). Such injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
  • hypothermia is the lowering of the core temperature of the body below normal level. Normal body temperature in an adult human measured rectally over 24 hours is 37 degree Celsius +/- 0.6 degree Celsius and is thus variable between individuals, and over time within the individual. Hypothermia as a medical condition is usually defined as the effects seen on the body once the core temperature drops below 35 degree Celsius. It may become critical, if the body temperature falls below 32 °C. In the present application hypothermia is defined as the lowering of the core body temperature below normal levels. This implies that any temperature below the normal core body temperature of the specific individual with its natural variations at the given point in time of the day, or period, herein is defined as being hypothermic. In particular, hypothermia is a temperature below 35.5 °C , such as below 35 °C, such as below 34.5 °C, such as below 34.0 °C.
  • Body temperature may be measured by a variety of means by mercury, electronic or plastic strip thermometers on different areas of the body such as the forehead, mouth, armpit, ear or rectum. It is presently understood, that the temperature referred to in the present application is the core body temperature, and that some of the above methods of measurement will indicate a different temperature than the core temperature.
  • induction of hypothermia in an individual can follow a predictable course and be responsive to the dose in which the combination of compounds capable of inducing hypothermia is administered.
  • the induction of the hypothermic condition may be rapid or slow depending on the situation of the individual in need of treatment. Also depending on the severity of the ischemic condition, it is of interest to provide a medicament for retaining the individual in the hypothermic state for variable durations of time.
  • a combination of compounds comprising one vanilloid receptor agonist and one cannabinoid or cannabimimetic compound may be used depending on dosage within a range of temperatures or for the induction of hypothermia to a specific temperature.
  • a combination of compounds, comprising at least one vanilloid receptor agonist and at least one cannabinoid and/or cannabimimetic compound may furthermore be used for an initial rapid decrease in core body temperature, and the subsequent maintenance of the reached temperature over a prolonged period. It is furthermore beneficial if the hypothermic state can be reversed in a rapid and controlled fashion either slowly or rapidly depending on the status of the individual.
  • the combination of compounds is capable of inducing hypothermia to any range of temperatures between 37 and 31 degree Celsius, such as between 36.5 and 31.5 degree Celsius, such as between 36 and 32 degree Celsius, such as between 35.5 and 32.5 degree Celsius, such as between 35 and 33 degree Celsius, such as between 34.5 and 33. 5 degree Celsius.
  • the ranges may furthermore be between 37 and 34 degree Celsius, such as between 36.5 and 34.5 degrees, such as 36 and 35 degrees, alternatively between 34 and 31 degree, such as between 33.5 and 31.5 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius.
  • the combination of compounds of the present invention is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, more preferably between 35 and 33 degree Celsius, and most preferably between 34 and 32 degree Celsius.
  • the combination of compounds of the present invention is capable of inducing hypothermia to any of the above specific temperatures within a range of +/- 0.5 degree Celsius, the range thus being between +/- 0.4 degree Celsius, such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius.
  • the temperature range or specific temperature a given combination of compounds is capable of inducing is herein also referred to as the target temperature of the combination of compounds and/or the medicament comprising the combination of compounds.
  • Combination of compounds consisting of a combination of one or more cannabinoid receptor agonists and one or more vanilloid receptor agonists, either as an integrated drug, administered simultaneously, or administered consecutively, is superior to any treatment based on the solitary use of any single cannabinoid receptor agonist or vanilloid receptor agonist.
  • a combination of compounds according to the present invention has a positive synergistic effect.
  • the positive synergistic effect putatively occurs by inducing several responses that converge, cross, or supplement each other. These responses may include a cross binding of the receptors, the activation of a larger number of receptors than possible with a single compound, activation of scores of co-receptors to either of the main receptors of the two classes of drugs and so on. It is surprising, that the combination of at least one vanilloid receptor agonist and at least one cannabinoid compound has an effect superior to either of the two classes of compounds on their own.
  • hypothermia depends on the characteristics of the individual compounds of the combinations and these characteristics may be to reach different target temperatures or different ranges of target temperatures, reaching the target temperatures at various speeds (varying peak effect times), the duration of the induced hypothermia, the lifetime of the active compounds, a minimizing of side effects and so on.
  • the medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly.
  • the medicament may furthermore comprise at least one compound that induces hypothermia over an extended time period, alternatively wherein at least one compound induces hypothermia for a short time period.
  • Cannabinoids and cannabimimetic compounds are a group of chemicals which activate the body's cannabinoid receptors, CB1 and CB2. Before other types were discovered, the term referred to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Cannabinoids are generally grouped into five classes based mainly on chemical composition and in part on origin:
  • the eicosanoids also referred to as endocannabinoids are produced in the bodies of humans and other animals •
  • Classical cannabinoids a group which includes natural cannabinoids found in larger or smaller amounts in the hemp plant Cannabis sativa.
  • Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence. Cannabinoids and cannabimimetic compounds (CB1/CB2 agonists) have furthermore received interest as putatively neuroprotective substances.
  • CB1/CB2 agonists cannabimimetic compounds
  • Cannabinoids are generally termed such due to their ability to bind one or more of the cannabinoid receptors CB1 and CB2.
  • CB1 and CB2 cannabinoid receptors
  • CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
  • CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the antiinflammatory and possible other therapeutic effects of cannabis.
  • hypothermia the behavioural effects, including hypothermia, seen when introducing animals to cannabinoids seems to be due to other factors besides CB1 receptor stimulation [46;49]. Inducing hypothermia by cannabinoids is therefore not solely equivalent to stimulating the CB1 receptor. Furthermore, there is evidence in the literature for other receptors than CB1 and CB2 as recipients of the cannabinoid ligands.
  • the receptors to which the cannabinoids and cannabimimetic compounds of the present invention may bind includes, apart from CB1 and CB2: a third CB receptor, herein termed CB3, GABA (gamma-aminobutyric acid) receptors, the NMDA (N- methyl- D-aspartate) receptor, the 5-HT(1 A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR) and TRPV1 (transient receptor potential vanilloid 1 ). It is furthermore within the scope of the invention that at least one compound of the combination of compounds of the invention may bind CB1 , CB2 or CB3 co-receptors. Compounds capable of binding any of the above-mentioned receptors thus fall within the scope of the present invention.
  • the cannabinoids of this application are, based on their structure, categorized as follows: classic cannabinoids, non-classic cannabinoids, aminoalkylindoles, eicosanoids (endogenous cannabinoids) and other compounds that fall out of the classification. Compounds belonging to any of these categories fall within the scope of the present invention.
  • At least one compound of the combination of compounds of the invention are capable of binding a cannabinoid receptor.
  • the present invention concerns the use of a combination of compounds wherein at least one compound comprises a structure of one of the general formulas illustrated in the below for cannabinoid and cannabimimetic compounds.
  • R is a chemical bond or a chemical moiety as defined in the above.
  • R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(d- 4 )-alkyl, heterocyclyl-(Ci.
  • any of the cannabinoid and/or cannabimimetic compounds of the invention may carry one or more phosphate groups bound as phosphate esters.
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a classic or non-classic cannabinoid comprising the general formula (I):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(C
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO 2 , phosphate,
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 .
  • R4 is selected from the group of: C, H, S, N, O, optionally substituted with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl- (Ci- 4 )-alkyl, heteroaryl-(d- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, substituted lower alkyl, alkyl such as (CrC x ) any of which may be further substituted with methyl, dimethyl, alkyl
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (I) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1 -CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (I) wherein R1 is C, optionally substituted with H, OH, OCH 3 or phosphate, when R2 is C substituted with C, O, OSO 2 , alkyl such as (C 3 -Cn) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrC x ), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted with C, ethyl, phosphate, alkyl such as (CrC 2 ) wherein C 2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate when R4 as defined in claim 8
  • the present invention also concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a classic or non-classic cannabinoid comprising the general formula (II):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with the C in the ring next to R5, optionally further substituted one or more times with C, S, N, O, OH, phenyl, phosphate, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO 2 , phosphate, alkyl,
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci_ 4
  • R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci_ 4 )
  • R5 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with R1 , optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_ 4 )-alky
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (II) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1 -CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 thus forming a ring, when R4 is C, N, O, P,
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (II) wherein R1 is C, optionally substituted with H, OH, OCH 3 or phosphate when R2 is C substituted with C, O, OSO 2 , alkyl such as (C 3 -C 8 ) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrC x ), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is O, OH, NH, optionally connecting with R4, when R4 is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn, when R5 is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH20H and wherein x is an integer of from 1 to 15.
  • R1 is C, optionally substituted with H,
  • R2 An additional element of importance for especially CB1 receptor recognition is the side chain of R2. It is preferably a lipophilic carbon chain comprising from 1 to 15 carbon atoms, preferably from 3 to 1 1 carbon atoms. It may have any number and type of substituents, especially methyl and/or dimethyl groups. The methyl groups are preferably close to the phenol group, as this appears to induce the greatest effect of the drug. Interestingly, it appears that shorter side chains increase the intensity and decrease the duration of the activity of these compounds.
  • the present invention concerns the use of a combination of compounds, wherein at least one compound is a cannabinoid or cannabimimetic compound such as an eicosanoids or other cannabinoid compound comprising the general formula (III):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl,0 heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(C
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, 5 cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, 0CH3, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroary
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula wherein R1 is (CI -C x ) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl or 0CH3 and wherein x is an integer of from 1 to 30.
  • R1 is (CI -C x ) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkyn
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (III) wherein R1 is (CrC x ), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substituted with C, CH20H, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH20H, CH2CI and wherein x is an integer of from 1 to 21.
  • a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (III) wherein R1 is (CrC x ), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substituted with C, CH20H, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH20H, CH2CI and wherein
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as an aminoalkylindole or other cannabinoid compound comprising the general formula (IV):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(C
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci)-al
  • R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci.
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein R1 is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH or phosphate, when R2 is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3, when R3 is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2, when R4 is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O,
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI -Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine when R4 is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
  • a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI -Cx) and wherein x is an integer
  • cannabinoid or cannabimimetic compounds specially relevant for the present invention include, but are not limited to classic cannabinoids such as (names in parenthesis are alternative names): delta-9-THC (Tetrahydrocanna-binol), delta-8-THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol-type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG, Cannabigerol-type CBG, Tetrahydrocanna-bivarin (THCV, THV), Tetrahydrocanna- binol- and cannabinol-type THC or CBN, Iso-Tetrahydro-cannabinol-type iso-THC, Cannabielsion-type CBE, Cannabicyclo l-type CBL, Cannabicitran-type CBT, HU- 308, JWH-
  • aminoalkylindoles such as: R(+)WIN55212, S(-)WIN-55213, JWH-015 and L-768242, eicosanoids / endogenous cannabinoids such as: Anandamide (arachidonyl ethanolamine), 2-Arachidonyl-glycerol (2-AG, Noladin ether), Palmitoylethanol-amine, Virodhamine (O-arachidonoyl-ethanolamine), Palmitoyl ethanolamide, Oleamide, other cannabinoid compounds such as: Arvanil,
  • Metanandamide, ACEA, ACPA, BAY 38-7271 and 0-1812. Phosphate derivatives of these compounds are especially relevant for the present invention.
  • cannabinoid or cannabimimetic compounds examples include anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate derivatives of these.
  • the compounds of the present invention may apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the cannabinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any adverse psychotropic effects.
  • the compound may furthermore have analgesic, anticonvulsive, anti-inflammatory, anti-anxiety, anti-nausea, pulse-lowering and blood- pressure modifying effects. Of these, it is preferable that the compound has analgesic effects.
  • a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
  • a preferred cannabinoid or cannabimimetic compound of the present invention is a compound capable of binding a cannabinoid receptor, such as CB1 , thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
  • Antagonists to cannabinoid and cannabimimetic compound function It is an object of the present invention to provide compounds that are capable of obviating the effect of the compounds that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the cannabinoids or cannabimimetic compounds herein described in binding to their receptors.
  • the purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
  • An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
  • antagonists includes but is not limited to: Rimonabant (SR141716, Acomplia, SR147778, SR141716A, SR144528, CP-272,871 , NIDA-41020, LY320135, AM251 , AM281 , AM630, WIN56098 and WIN54461.
  • Cannabinoids and cannabimimetic compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds in a medicament comprising a combination of compounds wherein at least one compound is a cannabinoid and/or cannabimimetic compound and at least one other compound is a vanilloid receptor agonist for the induction of hypothermia, especially for the induction of hypothermia in an individual suffering from ischemia or at risk of suffering from ischemia.
  • Vanilloid receptor agonists are a group of chemicals which are capable of binding the Vanilloid Receptor 1 (VR1 ), also known as the Transient Receptor Potential Cation Channel, Subfamily V (TRPV1 ).
  • the term vanilloid receptor agonist covers several groups of compounds including capsaicinoids and capsaicinoid-like compounds such as resiniferanoids and unsaturated dealdehydes.
  • capsaicinoid referred to a group of secondary metabolites produced by plants belonging to the genus Capsicum, such as chili peppers. These compounds are the active components of chili peppers that produce the sensation of burning in the mouth, when ingested.
  • Vanilloid receptor agonists may be divided into two classes based on origin and chemical composition:
  • Non-classical vanilloid receptor agonists a group wherein the members generally do not comprise a vanillamide moiety.
  • Vanilloid receptor agonists are irritants for mammals, but have no effect on birds, indicating that the compounds may have evolved as a deterrent for herbivores.
  • the various vanilloid receptor agonists have different pungencies as measured on the Scoville scale, with capsaicin and dihydrocapsaicin being the most potent of the classical vanilloid receptor agonists.
  • capsaicin as a medicament is known both anecdotally and scientifically and is today widely used as a medicine to treat or relieve various ailments.
  • the main clinical use of capsaicin is in the form of a topical ointment to successfully treat the pain of neuralgia such as caused by an infection with herpes zoster (shingles), diabetic neuropathy, rheumatism, fibromyalgia, various types of arthritis such as osteoarthritis or rheumatoid arthritis, and other forms of chronic pain.
  • Capsaicin desensitizes nerves from pain by eliminating unneeded nerve cells through necrotic death and helps arthritis sufferers by lowering the levels of Decapeptide Substance P (DSP) in the synovial fluid of joints. Capsaicin breaks down DSP, which can destroy cartilage and also magnify the sensing of pain. Recently studies demonstrate that capsaicin is a potent anticancer agent. Capsaicin induces apoptosis in pancreatic and prostate cancer cells with no significant damage to the surrounding healthy cells. Capsaicin is known to affect NF-kB, and it is believed that it is through this protein, that capsaicin activates apoptotic proteins, leading to cell death.
  • DSP Decapeptide Substance P
  • capsaicin containing candy provides significant pain relief of ulcers in the mouth which often develop in chemotherapy patients.
  • Capsaicin pastes and balms are used to treat muscle and joint pains and medications containing vanilloid receptor agonists are used as an anti-inflammatory agents as the chemicals causes blood vessels to dilate.
  • Capsaicin has furthermore been mentioned as a remedy to reduce serum cholesterol levels, relieve psoriasis and treat headaches, migraines and chronic sinus infections.
  • Vanilloid receptor agonists have furthermore received interest as putatively neuroprotective substances. The neuroprotective effect is at least in part mediated by induction of hypothermia, as described in the below.
  • vanilloid receptor agonist any compound which can be defined as a vanilloid receptor agonist, capsaicinoid or capsaicinoid-like compound these being classical or non-classical vanilloid receptor agonist or compounds that otherwise bind vanilloid receptors falls within the scope of the present invention.
  • vanilloid receptor agonist capsaicinoid or capsaicinoid-like are used interchangeably herein.
  • the sensation of burning pain elicited by vanilloid receptor agonists occurs by the selective activation of sensory neurons that convey information about noxious stimuli to the central nervous system.
  • the selectivity is based primarily on the presence of the VR1 / TRPV1 receptor, a nonselective cation channel to which the vanilloid receptor agonists, capsaicinoids and capsaicinoid-like compounds bind as agonists.
  • TRPV1 is also activated by extracellular protons, and temperatures in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
  • the vanilloid receptor agonists By binding to the TRPV1 receptor, the vanilloid receptor agonists produce the same effect that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin, without causing an actual chemical burn, is described as eliciting a burning sensation.
  • vanilloid receptor agonists A number of different mechanisms have been proposed to account for the various effects of vanilloid receptor agonists.
  • the vanilloid receptors that are likely to be multimeric, non-selective cation channels composed of 6 transmembrane domains, will upon activation induce Ca 2+ entry and subsequent release of sensory neuropeptides like calcitonin gene-related peptide (CGRP) and tachykinins (e.g. substance P) in addition to somatostatin.
  • CGRP calcitonin gene-related peptide
  • tachykinins e.g. substance P
  • the TRPV1 receptor was originally named the Vanilloid Receptor 1 (VR1 ), as a vanilloid moiety constitutes an essential component of classical vanilloid receptor agonists, but has since changed name to TRPV1 due to the receptors extended homology with other TRP family members.
  • TRPV1 is a member of the subfamily of TRPV receptors, which includes TRPV1 -6. Several of these receptors render the cells expressing them sensitive to heat at different intervals, mechanic pressure and various compounds such as vanilloid receptor agonists, camphor and others. Combinations of the subtypes and various oligomers of the vanilloid receptors may account for the variations in physiological outcome observed following activation of receptors by different vanilloid receptor agonists.
  • the oligomeric structure of the receptors increase the likelihood of discovering active substances with specificity for certain of the many organs that harbors vanilloid receptor agonists, thereby activating only parts of the vanilloid receptor system.
  • Vanilloid receptors are abundant in many organs of the body including neuronal tissues of the preoptic area, locus ceruleus, medial hypothalamus, reticular formation, and ventral thalamus. Vanilloid receptors have furthermore been found in non-neuronal "port of entry" tissues (e.g., skin, gut, airways, conjunctiva), the various cell types lining such tissues (i.e., keratin ocytes, epithelia, endothelia, etc.), and also in various peripheral non-neuronal tissues of rodents and humans (e.g., kidney, lung, testis, pancreas, spleen, liver, stomach, skin, vascular smooth muscle, placenta, cornea, uterus, and bladder).
  • the hypothalamus, with its abundance of vanilloid receptors, is of particular interest to this invention: It is a likely component in vanilloid receptor mediated hypothermia as it contains the temperature regulating centres of the CNS.
  • Receptors other than TRPV1 have been implicated in causing hypothermia upon binding of agonists hereto. Although some data suggests that capsaicin causes hypothermia by a cannabinoid receptor (CB1 and CB2) independent mechanism, there are hypothermia inducing vanilloid receptor agonists that are capable of interacting both with TRPV1 and especially CB2. Apart from TRPV3 mentioned above as a modulator of TRPV1 activity, the prokineticin receptors 1 and 2 (PKR1 and PKR2) have been shown to interact with TRPV1 and modulate its activity.
  • CB1 and CB2 cannabinoid receptor
  • Receptors to which the vanilloid receptor agonists, capsaicinoids and capsaicinoid- like compounds of the present invention may bind includes, apart from TRPV1 and the other TRPV subfamily members, TRPV2, -3, -4, -5 and -6, CB1 , CB2 and a third CB receptor, herein termed CB3, PKR1 and PKR2, GABA (gamma-aminobutyric acid) receptors, the NMDA (N-methyl-D-aspartate) receptor, the 5-HT(1A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR). It is furthermore within the scope of the invention that at least one of compound of the combination of compounds of the invention may bind TRPV1 co-receptors.
  • At least one compound of the combination of compounds of the present invention binds TRPV1 and/or a TRPV1 associated receptor.
  • TRPV1 receptor for the induction of hypothermia in mammals is the dramatic hypothermic response that is elicited by systemic administration of capsaicin, a response which is absent in mice lacking the TRPV1 gene.
  • vanilloid receptor agonists of this application are, largely based on their structure, categorized as follows: classic vanilloid receptor agonists and non-classic vanilloid receptor agonists. Compounds belonging to any of these categories fall within the scope of the present invention.
  • At least one compound of the combination of compounds of the invention are capable of binding the TRPV1 receptor and/or a receptor associated herewith.
  • the present invention concerns the use of a combination of compounds, wherein at least one compound is a vanilloid receptor agonist comprising a structure of one of the general formulas of vanilloid receptor agonists illustrated in the below.
  • R is a chemical bond or a chemical moiety as defined in the above.
  • R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, B, P, OH, CHO, hydrogen, alkoxy, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, heterocyclic group, heterocycloalkyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, phen
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist such as a classic or non-classic vanilloid receptor agonist comprising the general formula (I):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl
  • R2 is selected from the group of: C, S, N, O, optionally substituted one or more times with C, S, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, COOH, phenyl, amine (NH), halogen, alkoxy, substituted lower alkyl, alkyl or
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (CrC v ), or phenyl, any of which may be further substituted one or more times with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, acetyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, any of which may be further substituted with methyl, ethyl or phenyl and R2 is C, substituted one or more times with C, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, amine (NH), halogen, substituted lower alkyl
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with alkyl, alkenyl, any of which may be (C 4 -Cw) any of which may be further substituted one or more times with O, OH, acetyl, methoxy, ethoxy or methyl any of which may be further substituted one or more times with methyl, ethyl, cycloalkenyl or phenyl and w is an integer of from 5 to 18, and R2 is C substituted with either: cycloalkenyl further substituted at least twice with any of OH or methoxy, or: lower alkyl such as (CrC 2 ) at least once and further substituted one or more times with OH, COOH, Chloride, methyl or cycloalkenyl, optionally further substituted one or more times with OH or methoxy.
  • R1 is C substituted with al
  • the present invention furthermore concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist such as a non-classic vanilloid receptor agonist comprising the general formula (II):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alky
  • R2 is selected from the group of C, S, N, O, optionally substituted at least once with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or pheny
  • R3 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, hetero
  • R4 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, hetero
  • R5 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, CHO, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cyclo
  • R6 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, CHO, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH,
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with C, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alkyl, alkenyl
  • R4 preferably is C substituted with C, O, P, H, OH, phosphate, acetyl, alkoxy, alkyl, alkenyl, any of which may be (CrC v ), or phenyl, optionally substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate
  • R5 preferably is C substituted at least once with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl, any of which may be (CrC v ), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, methoxy, ethoxy, alkoxy or phosphate
  • R6 preferably is C substituted with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl, any of which may
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with alkyl or alkenyl which may be (C4-C z ), Boron, or heterocyclic group forming a ring with R6 thus comprising a pyrrolidine further substituted one or more times with O, methyl, alicyclic groups attached to one another, these being saturated or unsaturated or a heterocyclic group comprising said Boron, N and O, and being further substituted at least once with O, methyl or C further substituted at least once with cycloalkenyl, cycloalkyl, heterocyclyl further substituted at least once with O, OH, methyl, alkenyl, further substituted with lower alkyl and cycloalkenyl; R2 is C substituted with OH or hydrogen; R3 is C substituted with OH, methoxy, lower alkyl (C1 - C
  • the classical vanilloid receptor agonist compounds are preferable especially regarding the classical vanilloid receptor agonist compounds, as they seem to ensure a more favorable degree of vanilloid receptor activation.
  • These modifications include an unbranched alkyl side chain of a certain minimum length, as shorter chain analogues decrease in potency and thus are not capable of inducing hypothermia to a satisfactory degree.
  • the compounds of the present invention have relatively long alkyl or alkenyl chains (counted from R1 in the above formula) such as chains longer than 6 carbon atoms.
  • the length of the alkyl / alkenyl chain is between 6 and 25 carbon atoms, most preferably between 7 and 18 carbon atoms, even more preferably between 8 and 9 carbon atoms.
  • vanilloid receptor agonists examples include, but are not limited to classic vanilloid receptor agonists such as (names in parenthesis are alternative names): Capsaicin (C; 8-methyl-N-vallilyl-6- nonenamide), Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), Homocapsaicin (HC), Olvanil (N-9-Z- octadecenoyl-vanillamide), Rinvanil (vanillamide of ricinoleic acid), Arvanil (N- vanillylarachidonamide), PhAR (phenylacetylrinvanil), Nuvanil, Farvanil (vanillamide of farnesic acid), Ac-Rinvanil, Retvanil (vanillamide of retinoic acid), Nonivamide, and Ervanil (vanillamide of eruci)
  • non-classical vanilloid receptor agonist compounds specially relevant for the present invention include, but are not limited to compounds such as (names in parenthesis are alternative names): Resiniferatoxin (RTX), Anandamide (arachidonyl ethanolamine), N-arachidonoyldopamine (NADA), N-arachidonoyl-L- serine (ARA-S), Arachidonyl-2-chloroethylamide, 2-aminoethoxydiphenyl borate (2- APB), Evodiamine, Propofol, Isovelleral, Scutigeral, 12-hydroperoxyeicosatetraenoic acid, Alpha-sanshool, Beta-sanshool, Gamma-sanshool, Delta-sanshool, Alpha- hydroxy-sanshool, Beta-hydroxy-sanshool, Piperine, Zingerone, and Bv8.
  • RTX Resiniferatoxin
  • Anandamide arachi
  • vanilloid receptor agonist compounds may apart from inducing hypothermia induce secondary effects or have other characteristics. These may be related to the capsaicinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any blood-pressure modifying effects or induce hyperalgesic, nocifensive, plasma extravasation, peripheral vasodilatation, bronchoconstriction, bradycardia, or apnea effects among others. A potential analgetic effect may not be considered an adverse effect and may even, depending on the application of this invention, be desirable.
  • a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
  • a preferred vanilloid receptor agonist of the present invention is a compound capable of binding the TRPV1 receptor, thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
  • Examples of preferred or especially relevant vanilloid receptor agonists include: Capsaicin and compounds closely related to capsaicin such as: Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), and Homocapsaicin other specially relevant compounds include resiniferatoxin and compounds closely related hereto.
  • DHC Dihydrocapsaicin
  • NDHC Nordihydro-capsaicin
  • HDHC Homodihydro-capsaicin
  • Homocapsaicin other specially relevant compounds include resiniferatoxin and compounds closely related hereto.
  • Antagonists of vanilloid receptor agonist function It is an object of the present invention to provide compounds that are capable of obviating the effect of the vanilloid receptor agonists that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the vanilloid receptor agonists, capsaicinoids or capsaicinoid-like compounds herein described in binding to their receptors.
  • the purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
  • An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
  • antagonists include but are not limited to: 5-iodoresiniferatoxin, Aminoquinazoline (Aminoquinazoline 70), 6-iodo-nordihydrocapsaicin, IBTU (N-(4- cholorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea), KJM429 and JYL1421 , A-425619, AMG9810, SB 366791 , Adenosine and Capsazepine.
  • Vanilloid receptor agonists, capsaicinoids and capsaicinoid-like compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising a combination of compounds wherein at least one compound is a vanilloid receptor agonist and at least one other compound is a cannabinoid and/or cannabimimetic compound for the induction of hypothermia in an individual suffering from ischemia or at risk of suffering from ischemia.
  • the induction of hypothermia by any combination of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising a combination of at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound.
  • the medicament of the present invention thus comprises a combination of compounds for the induction of hypothermia in an individual for the treatment and/or prophylaxis of ischemia in said individual.
  • composition Whilst it is possible for the compounds or salts of the present invention to be administered as the raw chemical, it is preferred to present them in the form of a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation, for medicinal application, which comprises a combination of compounds of the present invention or pharmaceutically acceptable salts thereof, as herein defined, and a pharmaceutically acceptable carrier there for.
  • the combinations of compounds of the present invention may be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise the combinations of compounds of the invention or their pharmaceutically acceptable salts or a crystal forms thereof as the active components.
  • the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
  • the combinations of compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or non-aqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta.-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more non-ionic surfactants having a hydrophile - lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile - lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • salts of the instant compounds where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • compositions are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.
  • the combination of compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • a pharmaceutically acceptable salt means any salt of the compounds mentioned.
  • it means a pharmaceutically acceptable acid addition salt.
  • Pharmaceutically acceptable acid addition salts of the compounds include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydrobromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • An aspect of the present invention regards the pH of the medicament.
  • the pH of the medicament depends on the administration form, as the pH of the medicament preferably is suitable for the route of administration chosen.
  • An embodiment of the present invention comprises a medicament wherein the pH of the composition is between pH 5 and pH 9, such as between pH 5.5 and 8.5 such as between pH 6 and 8, such as between pH 6.5 and 7.5. Most preferably the pH of the medicament is in accordance with the route of administration and the tissue to which the medicament is administered.
  • the invention provides a combination of compounds for the production of a medicament for the treatment of ischemia in an individual. Ischemia may arise due to various circumstances and thus it is an object of the present invention to treat ischemia arising from a plurality of medical indications.
  • cardiovascular diseases such as myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
  • Target temperature and peak effect The target temperature of the medicament is the core body temperature that can be reached upon administering the medicament according to the present invention as prescribed according to potency, dosage and so on.
  • Various ranges and specific hypothermic core body temperatures that fall within the scope of the present invention are equal to the temperatures that the combinations of compounds themselves may induce as listed in the section on hypothermia.
  • An embodiment of the present invention is thus a medicament capable of inducing hypothermia below 36 °C, such as below 35.5 °C, such as below 35 °C, such as below 34.5 °C, such as below 34.0 °C in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius.
  • the combinations of compounds of this invention will often show a peak in hypothermia inducing effect 30 minutes to 120 minutes after administration, but may potentially peak sooner or later than described by this interval.
  • the hypothermia inducing effect will frequently last from 1 hour to 12 hours, but may potentially last shorter or longer than described by this interval.
  • the main routes of drug delivery, in the treatment method are intravenous, oral, and topical, as will be described below.
  • Other drug-administration methods such as subcutaneous injection or via inhalation, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
  • the mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the individual to which the biologically active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, preferably the mucosa of the nose, mouth or rectum.
  • Combinations of compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, intraspinal, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the combinations of compounds may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the combinations of compounds according to the invention may be administered with at least one other compound.
  • the compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
  • a preferred embodiment of the present invention is a medicament for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. More preferably the administration form is by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
  • a medicament comprising a cannabinoid is by intravenous injection.
  • Intravenous injection is also the preferred mode of administration of medicaments comprising vanilloid receptor agonists, as these may act as irritants under certain circumstances. Therefore, the combinations of compounds of the present invention, depending on the specific active substances, may preferably be administered as capsules rather than tablets or suppositories, and preferably as intravenous injections rather than subcutaneous or intramuscular injections.
  • the individual that may benefit from the administration of a medicament as described herein may be an individual suffering from ischemia or at risk of suffering from ischemia. If the individual is at risk of suffering from ischemia the preferred administration form of the medicament may be suppository, oral administration or inhalation. Preferably, the individual is an individual suffering from ischemia.
  • the preferred administration form for an individual suffering from ischemia is an injection, such as an intravenous, intramuscular, intraspinal, intraperitoneal or subcutaneous injection.
  • the individual may be any human being, male or female, infant or old.
  • the ischemic condition to be treated or prevented in the individual may relate to the age of the individual, the general health of the individual and whether or not the individual has a prior history of suffering from diseases or disorders that may have or have induced ischemic conditions in the individual.
  • Dosage The dosage of the combinations of compounds according to the invention depends on the combination in question; however, the amount of the combination is also closely related to the pharmaceutical composition of the medicament, any third or more compound of the medicament or any second active ingredient of the medicament.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen will be from about 0.001 to about 80 mg/kg of total body weight.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen will be from about 0.01 to about 2,400 mg/kg of total body weight, preferably, the dosage of the medicament according to the present invention is between 10 ⁇ g to 10mg pr kg total body weight, such as between 100 ⁇ g to 1 mg pr kg total body weight, depending on the compound of choice. It has been found that cannabinoids and vanilloids varies with respect to potency and affinity for the receptor as well as with respect to molecular weight.
  • the exact dosage may be calculated based on the porcine study model described in Example 14.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a combination of compounds, alone or in together with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
  • the specifications for the unit dosage forms of the present invention depend on the particular combination employed and the effect to be achieved, as well as the pharmaco-dynamics associated with each of the compounds of the combination in the host.
  • the dose administered should be an " effective amount” or an amount necessary to achieve an "effective level" in the individual patient.
  • the effective level is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics, drug distribution, and metabolism.
  • the "effective level” can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more combinations according to the invention.
  • the effective level can also be defined as the amount needed pr kg body weight, in other words the concentration, required to reach the peak effect for a specific combination of compounds.
  • the effective level depends on the severity of the ischemic condition, such as total amount of tissue experiencing hyp- or anoxia, the duration of the ischemic condition, whether it is the first or a subsequent ischemic attack of the individual and so forth.
  • the dosage of the medicament according to the present invention is between 10 ⁇ g to 80 mg pr kg total body weight, such as between 100 ⁇ g to 1 mg pr kg total body weight.
  • the medicament may be administered in any suitable dosage regime, suitable as to the potency of the combination of compounds / the drug, the target temperature to be reached, the speed of action of the combination, the metabolic stability of the combination, the duration of the treatment and how often the medicament optimally is to be administered.
  • a medicament to be administered at intervals of 30 minutes to 48 hours such as intervals of 1 to 47 hours, 2 to 45 hours, 3 to 43 hours, 4 to 41 hours, 5 to 39 hours, 6 to 37 hours, 7 to 35 hours, 8 to 3 hours, 9 to 31 hours, 10 to 29 hours, 1 1 to 27 hours, 12 to 25 hours, 13 to 23 hours, 14 to 21 hours, 15 to 19 hours 16 to 18 hours.
  • a medicament to be administered at intervals of 30 minutes to 24 hours such as 1 to 23 hours, 2 to 22 hours, 3 to 20 hours, 4 to 18 hours, 5 to 16 hours, 6 to 14 hours, 7 to 12 hours or 8 to 10 hours.
  • the administration occurs at intervals of 1 to 6 hours, such as 2 to 5 hours, 3 to 4 hours.
  • the optimal administration interval depends on the duration of the hypothermic treatment.
  • the duration of the treatment depends among other things on the severity of the ischemic condition. It is within the scope of the present invention to provide medicaments for the induction of hypothermia wherein the duration of the treatment is from 6 to 72 hours, such as from 7 to 69 hours, such as from 8 to 66 hours, 9 to 63 hours, 10 to 60 hours, 1 1 to 57 hours, 12 to 54 hours, 13 to 51 hours, 14 to 48 hours, 15 to 45 hours, 16 to 42 hours, 17 to 39 hours, 18 to 36 hours, 1 to 35 hours, 20 to 32 hours, 21 to 29 hours, 22 to 26 hours 23 to 25 hours.
  • the duration of the treatment is between 6 and 48 hours, more preferably between 6 and 24 hours.
  • the medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly.
  • rapidly means within few hours, such as within 2 hours, such as within 1 hours, whereas slowly means after several hours.
  • An embodiment of the present invention is a pharmaceutical composition comprising a combination of compounds as herein described and furthermore comprising a second active ingredient.
  • the second active ingredient may increase the hypothermic effect of the combination of compounds of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
  • the second active ingredient may thus be selected from the non-limiting group of: neurotensins, analgesics, opiods, GABAs and adrenergic antagonists. Examples of these include, but are not limited to: neurotensin analogues KK13 and KK14.
  • kits of parts comprising at least one pharmaceutical composition according to any of the above, a means for administering said vaccine and the instruction(s) on how to do so. It is within the scope of the present invention to include multiple dosages of the same composition or several different compositions.
  • the kit of parts further comprises a second active ingredient. Examples
  • a 57-year-old woman is taken care of by the ambulance staff that finds her in ventricular fibrillation approximately 5 minutes after having collapsed without warning.
  • the patient is immediately defibrillated and spontaneous circulation and ventilations occurred.
  • On arrival to the hospital 21 minutes after having collapsed, the patient has a palpable pulse.
  • Staff at the emergency room has been alerted in advance.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • Hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1 .
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • the physician present in the ambulance team decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 66-year-old man is undergoing elective heart surgery. He suffers from irregular cardiac rhythm during the procedure and goes into cardiac arrest with much impaired circulation for 6 minutes after which the surgical team manages to restore circulation. Subsequent to restoration of circulation, the surgeon in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • An intravenous bolus injection of HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. 40 mg/kg body weight
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • Example 4 Cardiac arrest An electrician accidentally receives a high-voltage jolt and immediately slips into a coma. The company physician manages to resuscitate the cardiac arrest patient after just 7 minutes. The patient is rushed to hospital where the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
  • a newborn baby suffers cerebral ischemia during delivery as the umbilical cord gets wrapped around his neck.
  • the APGAR score 10 minutes after delivery is 6.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • Hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and 2.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 10O microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. 10O microgram/kg body weight
  • HU-210 e.g. 10O microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. 10O microgram/kg body weight
  • a third cannabinoid agonist e.g. 40 mg/kg body weight
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 78-year-old woman is admitted to hospital 50 minutes after experiencing sudden onset lack of mobility of the left arm and leg and as well and difficulties speaking.
  • the patient is diagnosed with a stroke.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • An intravenous bolus injection of HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. 40 mg/kg body weight
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • Example 8 Stroke A 29-year-old man suffers continuous pains in the back of his head for two weeks after which he suddenly collapses and slips into a coma. The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
  • a 55-year-olm man is admitted to hospital 18 minutes after experiencing nausea, shortness of breath, and severe chest pains.
  • the patient who is suffering myocardial infarction is evaluated by the physician in charge who decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the heart and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 60-year-old woman is feeling rather well two days after major surgery when she suddenly slips into a coma. Following acute surgery, brought on by a pulmonary embolism, she is stabilized. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • the purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • Type of rabbits New Zealand White, Charles River
  • Type of temperature probe PC Based pyrogen testing system, Ellab APT 91
  • Modulation of CB and TRPV1 activities will be assessed in vitro by measuring cannabinoid and/or cannabimimetic compound and vanilloid receptor agonist induced Ca2+ flux, respectively. This will be done using FLIPR and HEK293 cells stably expressing recombinant human (h) and rat (r) TRPV1 (hTRPVI -HEK293 and rTRPV1 -HEK293, respectively) and recombinant human (h) and rat (r) CB receptors (hCB1 -HEK293, hCB2-H293, rCB1 -HEK293 and rCB2-H293) and especially in cells co-expressing human or rat TRPVI and CB receptors (hTRPVI -hCB1 -HEK293 and hTRPVI -hCB2-HEK293).
  • Intracellular Ca2+ levels will be measured in CB, TRPV1 and coCB/TRPV1 -expressing cells during exposure to compounds and combinations of compounds. A concentration dependent increase in Ca2+ influx will be observed.
  • the efficacy of vanilloid agonists will be estimated by comparing these to the maximum response induced by capsaicin, likewise the efficacy of cannabinoids will be estimated by comparing these to the maximum response induced by cannabidiol.
  • a combination of capsaicin and cannabidiol will be used as reference for measuring combinations of drugs.
  • the compound may be tested in the porcine study model.
  • the porcine model is used because the body weight of the pigs is comparable to the body weight of humans.
  • the efficacy of a compound tested in the porcine model may be correlated with the efficacy of the cannabinoid or vanilloid compound tested in the same porcine study model.
  • the evaluation is carried out on "dansk landrace" pigs with a body weight of 70-90 kilo.
  • the pigs will not be sedated; they will be fed twice a day; and they will be subjected to a day cycle consisting of 12 hours of light followed by 12 hours of dark.
  • the compound investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection. o
  • Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study.
  • the probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required read- outs.
  • Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
  • the minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose of compound or compound mixture.
  • Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration.
  • Yamashita K, Eguchi Y, Kajiwara K, lto H Mild hypothermia ameliorates ubiquitin synthesis and prevents delayed neuronal death in the gerbil hippocampus. Stroke 1991 ; 22(12):1574-1581.
  • KiI HY Zhang J, Piantadosi CA: Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 1996; 16(1 ):100-106.
  • Postischemic hypothermia attenuates apoptotic cell death in transient focal ischemia in rats. Acta Neurochir Suppl 2000; 76:525-527.

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Abstract

La présente invention concerne l'induction d'une hypothermie chez l'homme, de manière prévisible et sensible à la dose, au moyen d'une composition pharmaceutique comprenant une combinaison (1) d'agonistes des récepteurs des vanilloïdes, de capsaicinoïdes ou d'agonistes de type capsaicinoïdes atteignant les récepteurs des vanilloïdes et se liant à ceux-ci, et (2) de cannabinoïdes ou d'agonistes cannabimimétiques atteignant les récepteurs des cannabinoïdes et se liant à ceux-ci, ce qui permet d'induire une hypothermie bénéfique pour les patients souffrant de maladies caractérisées par une anoxie tissulaire.
PCT/DK2007/050138 2006-10-04 2007-10-04 Utilisation d'une combinaison de médicaments induisant une hypothermie WO2008040361A2 (fr)

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WO2009124551A2 (fr) * 2008-04-09 2009-10-15 Neurokey A/S Utilisation de médicaments induisant une hypothermie
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WO2009071094A2 (fr) * 2007-12-05 2009-06-11 Neurokey A/S Traitement par combinaison d'effets ischémiques
WO2009071094A3 (fr) * 2007-12-05 2009-08-06 Neurokey As Traitement par combinaison d'effets ischémiques
WO2009124552A2 (fr) * 2008-04-09 2009-10-15 Neurokey A/S Utilisation d’une combinaison de médicaments induisant une hypothermie
WO2009124551A2 (fr) * 2008-04-09 2009-10-15 Neurokey A/S Utilisation de médicaments induisant une hypothermie
WO2009124551A3 (fr) * 2008-04-09 2009-12-03 Neurokey A/S Utilisation de médicaments induisant une hypothermie
WO2009124552A3 (fr) * 2008-04-09 2009-12-17 Neurokey A/S Utilisation d’une combinaison de médicaments induisant une hypothermie
WO2010015260A2 (fr) * 2008-08-07 2010-02-11 Neurokey A/S Administration par infusion pour le traitement d’effets ischémiques
WO2010015260A3 (fr) * 2008-08-07 2010-06-17 Neurokey A/S Administration par infusion pour le traitement d’effets ischémiques
US8604053B2 (en) 2008-10-17 2013-12-10 Abbvie Inc. TRPV1 antagonists
US8609692B2 (en) 2008-10-17 2013-12-17 Abbvie Inc. TRPV1 antagonists
WO2012134943A1 (fr) 2011-03-25 2012-10-04 Abbott Laboratories Antagonistes de trpv1
US8802711B2 (en) 2011-03-25 2014-08-12 Abbvie Inc. TRPV1 antagonists
WO2013096226A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
WO2013096223A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
US8859584B2 (en) 2011-12-19 2014-10-14 Abbvie, Inc. TRPV1 antagonists
US8969325B2 (en) 2011-12-19 2015-03-03 Abbvie Inc. TRPV1 antagonists
EP2614727A1 (fr) * 2012-01-10 2013-07-17 Symrise AG N-nonanoylvanillylamine comme moyen de réduction de l'appétit, comme moyen de transmission d'une sensation de satiété et en tant qu'améliorateur d'humeur ainsi que mélange de matière associé, produits consommables oralement et procédé
US8796328B2 (en) 2012-06-20 2014-08-05 Abbvie Inc. TRPV1 antagonists

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